This time around, we were lucky enough to have Dr. Alex Solyom join us for the pod. Dr. Solyom is the senior medical director at Enzyvant, where he and the team research a new therapy for an ultra-rare disease called Farber disease, which manifests itself through three cardinal symptoms: The first, nodules, or hard bumps under the skin; the second is joint contractures; and the third, a hoarse or weakening voice.

As we chatted, we touched on a few things, and we touched on the benefit a genetic test could provide for patients who are curious to know if their symptoms point to a genetic disorder. So, if the symptoms we talk about sound familiar to you, or seem like symptoms you've seen them in the life of a loved one, and you're curious about a genetic test, please contact us at, where we'll be able to help guide you to the test if appropriate.

Without further ado, here is my conversation with Dr. Alex Solyom of Enzyvant.

Aaron: We have Alex Solyom, senior medical director of Enzyvant, where he's researching a treatment for the ultra-rare disease Farber disease. Alex, thanks for making the time.

Dr. Solyom: I'm happy to talk about this, and I'm glad you invited me to be on the show.

Aaron: From our last conversation, I understand that a Farber patient's journey can vary pretty much with every single person who has it. Can you revisit what Farber disease is and how it physically represents itself?

Dr. Solyom: Farber disease is a rare disease. It's caused by an enzyme deficiency and the buildup of a material in cells that is a result of that enzyme deficiency. That material is called ceramide, and it causes an inflammatory reaction which leads to symptoms that resemble the symptoms that arthritis patients have to a large part, so joint inflammation, joint pain, the inability to move joints normally which we call contractures, and then also these nodules on the surface of the skin and also around the joints.

Those are what we call granulomas, so they are basically a bunch of inflammatory cells that are drawn to a certain area. They can also be painful and red and impair the normal function of the joint and the use of the fingers and the hand and the feet and in everyday life. These same types of nodules can form on the vocal cords, and so you can have hoarseness also as a part of Farber disease, or just a weak voice, even if it's not a really hoarse, raspy voice.

Then it can also be, in some cases, particularly in the more aggressive forms of Farber disease, with more rapid progression, you can have central nervous system disease and some other symptoms as well. But generally, those symptoms that resemble inflammatory joint disease and arthritis, those are the ones that are typically found in Farber disease.

Aaron: How does genetic testing play into this? How does that help a patient identify why they might be experiencing a certain symptom?

Dr. Solyom: The enzyme deficiency that causes Farber disease is a result of a mutation in a particular gene, or two mutations, and in two copies of the gene. This is the ASAH1 gene. Genetic testing can help by providing a first step in establishing a diagnosis or ruling out the possibility of a particular diagnosis in diseases like this.

Of course, it always has to be done through a physician or a genetic counselor who is able to provide a good interpretation of the test, but genetic testing is now, in the times we're living in now, it can be done relatively quickly and relatively easily with something as simple as a dried blood spot card or a swab from the cheek, a couple of cells off the inside of the cheek. Then you have, if not an answer in all cases, at least a good direction as to whether you should suspect Farber disease or not.

Aaron: Speaking of those directions, what are some of these typical indicators that one might see when the results of this test come in?

Dr. Solyom: When the results of the test come in, you look for the particular mutations that would be likely to cause an enzyme deficiency, and I think that if you're testing or having a test done early on when there may not be a clear picture or maybe not all the symptoms have appeared yet, then the results of the genetic test can make sure that a physician or whoever else is in charge of the care of the patient, they can pay attention to potential development of other symptoms like this.

Aaron: Joint pain's relatively common, and especially compared to something like nodules under someone's skin. Both are cardinal symptoms of Farber disease, correct?

Dr. Solyom: Yes.

Aaron: What steps can be taken in educating patients about their joint pain, whether it's a symptom that could point to Farber ... So what challenges are typically faced in working with patients to determine whether something as common as joint pain could be or should be investigated further?

Dr. Solyom: This is all part of a discussion with the physician in charge of the care of the patient, I think. The key is for a physician, I think, or for health care providers in general, to look for the atypical path or progression of the disease or the symptoms. If the joint pain doesn't fit into a particular category that's very familiar, then you can look for the less familiar or the less common explanations for that joint pain or for that joint disease or for the nodules.

I think that the question of searching for a diagnosis for a rare disease or a less common cause of a particular set of symptoms is ... I think it should come once the more common reasons for joint pain and other symptoms have been addressed and considered, but it's important to also make sure that you're thinking about the possible other explanations that might be caused by other rare diseases, and this is the dilemma or the challenge that faces physicians and patients, I think, in general, in trying to diagnose rare diseases.

Aaron: It's kind of science meets the art.

Dr. Solyom: Yeah. It's about balancing the likelihood of something happening with keeping your mind open to the fact that there may always be an explanation that's unique or maybe not what you see in the everyday.

Aaron: On the same line, for some patients, it's pretty difficult to determine whether a symptom's notable enough to report or severe enough to report, so an example, many people would report nodules but not joint pain or a hoarse voice, because the latter two are so common to their everyday lives that they might not even think to report them in conjunction with something new and rare like nodules. Obviously, upon direct interaction, a significant number may reveal that they also live with joint pain or hoarse voices, but not necessarily in that first interaction.

What are some tips that you might provide from your perch in navigating the challenge of patients who have accepted, to some degree, this level of quotidian pain, this daily discomfort?

Dr. Solyom: Yeah, that's always a difficult question. I worked for quite some time in a clinic as a pediatrician and it's always something to consider when you're talking to a patient as a physician that they may be living with a symptom for some time and that they might not consider it worth reporting or they may simply forget about it because it isn't the most important thing on that particular day.
I think that when a patient is thinking about how they describe their symptoms, then it's ... And on the physician's side, the same thing ... It's important not to take anything for granted and to consider that each of these symptoms may not be independent of one another and it's likely that if someone has ... At least, this is what I was taught and what I experienced as well, working as a doctor, that if someone has five symptoms or six symptoms or seven symptoms, it's more likely that they have one disease that explains the majority of those symptoms rather than seven different diseases explaining each one of them independently.

You asked about what could be a guide to navigate or negotiate these things. I think that thinking of a lot of symptoms together probably or may indicate a disease that can explain all of them, so it's important to always make sure that you're addressing those, any concerns, to the physician.

Aaron: In one of our previous conversations, you mentioned that joint contractures are the most unusual of the cardinal symptoms that a Farber disease patient might have, and that Farber disease itself is a progressive condition, while something like juvenile idiopathic arthritis ... Did I get that right? Judeo ... Yeah. Which is the common misdiagnosis of Farber, is cyclical. Could you elaborate on why the contractures themselves are so unusual in relation to the other symptoms and how the progressive nature of Farber plays into all of this?

Dr. Solyom: I think the contractures existing for a long time, so chronic contractures are not common in JIA but they would be common in Farber, so having contractures is pretty common in Farber. This is one of the things that would distinguish it from JIA, because with the treatments that exist nowadays, you're generally expected, a majority of JIA patients would respond to one of those treatments at least and prevent them from developing the kind of joint disease that would lead to contractures. Contractures, again, being the lack of the ability to move your joint in a normal way.

I think that it's important that, for example, if you have a JIA ... Considering a JIA patient, and this is what's been shown in the literature, and by other physicians who care for Farber patients, that many of the patients who were initially diagnosed with JIA and who ended up with Farber, they had a progressive course of disease that didn't respond adequately to the treatments that were applied, and so they developed in a pretty clear progression rather than responding and then getting worse as a JIA patient might respond to treatment and then have a disease flare and then receive another treatment and then be better for a while and have another disease flare. In Farber, it's generally a progression, and the rate of that progression is what changes. The contractures are pretty common in Farber. They would be less common in JIA.

Aaron: Got it.

Dr. Solyom: If that's what I said before, I might have misstated it, but I meant to say that contractures are ... If you have contractures over the long term in a JIA patient, that may be an indication for a testing for Farber, for example.

Aaron: It goes back to that thing you were saying about one disease explaining multiple symptoms versus multiple diseases explaining one symptom each, that sort of thing?

Dr. Solyom: Right.

Aaron: Many people become more involved in their diagnoses because they're predominantly worried about something uncommon like nodules, and then they indicate later on, like we said, that they've lived with joint pain or a hoarse voice, or what have you, but that it was the emergence of the bumps under their skin that motivated them to research what might be happening, because it was so uncommon.

Is there a medical reason why nodules might present later in a patient's life, even if they've been living with relatively mild cases of Farber disease?

Dr. Solyom: I think that you bring up a very good point, that the presentation of symptoms in Farber disease is itself a variable. There isn't a strict order to whether you develop joint symptoms and then nodules and then a hoarse voice or the other way around. In fact, it can take up to three years, or in the cases that we know, but certainly an extended period of time for all the symptoms, all the cardinal symptoms, to appear together.

I think that the fact of the occurrence of nodules is not necessarily earlier or later in the course of the disease, doesn't necessarily relate to whether the disease was more or less severe. It is part of the normal development of the disease as far as we understand the inflammatory response to the storage of this material and the enzyme deficiency.

I think that, as I said, we've seen that one of the challenges, in addition to simply the symptoms developing over a longer period of time, is that, of course, the severity of each symptom can vary between patients or among patients. For example, if a patient had, let's say, four or five or six nodules or 10 nodules that were relatively small and not necessarily causing immediate discomfort, then it may take some time for that to be recognized as a symptom as well, so this can cloud the picture. There may have been nodules that appeared but didn't reach the point of a real concern until a later date.

A discalimer: Nothing stated in this podcast is intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.

A big thank you to Dr. Alex Solyom for chatting with us as part of our collaboration with Enzyvant. This is a sponsored podcast.